During the past decade, the discovery of kisspeptin peptides and their cognate receptor KISS1R has expanded our mechanistic understanding of the hypthothalamic-pituitary-gonadal (HPG) axis. The kisspeptin system has been shown to be an integrator of several streams of biological feedback (endocrine, metabolic, circadian) and regulates the pulsatile secretion of GnRH, which subsequently controls the release of the gonadotropins LH and FSH. Gonadotropin activity dictates a host of biological responses, including gonadal development, puberty, fertility, gametogenesis, and sex hormone production. Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women of reproductive age. Infrequent and/or prolonged menstrual periods, acne, aberrant hair growth (due to associated hyperandrogenism), insulin resistance, and obesity can all occur in women with PCOS. Commonly, menstrual abnormality signals the onset of the condition in adolescence, though PCOS may manifest later following unexplained weight gain and/or difficulty becoming pregnant. Current treatments rely on managing the symptoms of the disease rather than the cause. Recent evidence demonstrates that a hallmark of the pathology of PCOS is hyperpulsatility of GnRH secretion. Thus, as the gatekeeper of the HPG-axis and GnRH pulsatility, KISS1R is an attractive new mechanism for treating the neuroendocrine cause of PCOS. KISS1R antagonists should dampen GnRH pulsatility and offer the first possibility of treating the disease at the hypothalamic level, while minimizing the potential risk of hypoestrogenemia. During our Phase I program, we were able to develop the medicinal chemistry strategy and pharmacologic methodology to determine the activity of KISS1R antagonists. This resulted in non-peptides with good potency and none of the physicochemical liabilities of the only series of previously published antagonists. We were able to extend the goals of our Phase I program to include an initial characterization of selectivity, pharmacokinetics, and pharmacodynamics of a lead molecule. Our Phase II plan is to use pharmacology, receptor structural models and medicinal chemistry to further develop these antagonists in terms of potency, selectivity, oral bioavailability (as well as other drug-like properties), and efficacy in animal models of HPG axis control and pulsatility. If successful, his project will result in the selection of a drug candidate for pre-IND enabling toxicology studies to support first-in-human studies. Ultimately, this molecule would be evaluated in later stage clinical trials as a potential First-In-Class treatment for women with PCOS and other reproductive disorders.